A novel UPLC-MS/MS method for simultaneous quantification of trigonelline, 4-hydroxyisoleucine, and diosgenin from Trigonella foenum-graecum extract: Application to pharmacokinetic study in healthy and type 2 diabetic rats.

Trigonelline (TR), 4-hydroxyisoleucine (4-HI), and diosgenin (DG) are the main bioactives of the purified standardized extract of the popular plant Trigonella foenum-graecum L. (TFG), and it has been proven effective for the treatment of various diseases. However, to the best of our knowledge, no study has investigated the pharmacokinetic parameters of purified standardized T. foenum-graecum extract in normal and diabetic Wistar rats. The present study has developed and validated a rapid, reliable, and sensitive simultaneous ultra-performance liquid chromatography MS method to estimate these bioactives. The chromatographic separation was achieved using methanol, acetonitrile, and 0.1% formic acid with the ideal gradient flow system on a BEH Shield RP 18 column. A positive electrospray ionization mode was selected to estimate m/z values of TR (138.14 > 94.63), 4-HI (148.19 > 74.08), and DG (415.54 > 271.33). The method was robust and reproducible over the linearity range of 60-5000, 6-5000, and 15-5000 ng/mL for TR, 4-HI, and DG, respectively. Using this novel validated method, we investigated the pharmacokinetic parameters of bioactives using Phoenix WinNonlin version 8.0 (Certera) in normal and diabetic rats. The assay was successfully applied for the estimation of pharmacokinetic parameters using noncompartmental analysis. This investigation shows that the absorption rate increased, whereas distribution and elimination processes slowed down in diabetic rats compared with normal rats.

Safety and clinical effectiveness of Withania Somnifera (Linn.) Dunal root in human ailments.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera popularly known as Aswagandha or Indian Ginseng/Poison Gooseberry have thousands years of history of use in Indian traditional medicine. Besides, finding place root of the plant as Indian Ginseng, Ayurveda also uses root of this plant as general health tonic, adaptogenic, nootropic, immunomodulatory etc. With its widespread and growing use, it becomes prudent to scientifically evaluate and document both the efficacy and safety of this plant in humans. AIM OF THE STUDY: Aswagnadha root is rapidly gaining popularity abroad for use as medicine. Current article attempts to primarily review the human efficacy and safety of Aswagandha generated through clinical trials. METHODS: A systematic search both for indexed and non-indexed literature was made for W. somnifera using various search engines and databases and the details of research articles pertaining to all clinical trials/human studies, animal studies addressing safety issues of CNS, CVS, general toxicity, mutagenicity, genotoxicity, reproductive safety and herb-drug interactions were reviewed and compiled comprehensively from full texts. RESULTS: A total of 69 (39 pre-clinical and 30 clinical) studies documenting efficacy and safety aspects were identified and the desired information of these studies is comprehensively presented in this review. Retrieved thirty(30) human studies demonstrated reasonable efficacy of root preparations in subclinical hypothyroidism (1), schizophrenia (3), chronic stress (2), insomnia (2), anxiety (1), memory and cognitive improvement (2), obsessive-compulsive disorder (1), rheumatoid arthritis (2), type-2 diabetes (2), male infertility (6), fertility promotion activity in females (1), adaptogenic (3), growth promoter in children (3) and chemotherapy adjuvant (1). Reasonable safety of root preparations of Aswagandha has been established by these retrieved 30 human trials. No serious adverse events or any changes in haematological, biochemical or vital parameters were reported in these human studies. Only mild and mainly transient type adverse events of somnolence, epigastric pain/discomfort and loose stools were reported as most common (>5%); and giddiness, drowsiness, hallucinogenic, vertigo, nasal congestion (rhinitis), cough, cold, decreased appetite, nausea, constipation, dry mouth, hyperactivity, nocturnal cramps, blurring of vision, hyperacidity, skin rash and weight gain were reported as less common adverse events. Pre-clinical chronic toxicity studies conducted up to 8 months also found root extracts to be safe. No mutagenicity or genotoxicity was reported for the root; only mild CNS depression and increase in thyroxine (T4) levels were reported with rootby some studies. Further, there was no in vitro and in vivo inhibition seen for CYP3A4 and CYP2D6, the two major hepatic drug metabolizing enzymes. CONCLUSION: Root of the Ayurvedic drug W. somnifera (Aswagandha) appears a promising safe and effective traditional medicine for management of schizophrenia, chronic stress, insomnia, anxiety, memory/cognitive enhancement, obsessive-compulsive disorder, rheumatoid arthritis, type-2 diabetes and male infertility, and bears fertility promotion activity in females adaptogenic, growth promoter activity in children and as adjuvant for reduction of fatigue and improvement in quality of life among cancer patients undergoing chemotherapy. Properly designed, randomized-controlled, large-size, prospective trials with standardized preparations are needed to ascertain efficacy of Aswagandha root in previously studied and other new indications.

Pre-clinical pharmacokinetic and pharmacodynamic modelling study of 4-hydroxyisoleucine using validated ultra-performance liquid chromatography-tandem mass spectrometry.

A reliable and sensitive ultra-performance liquid chromatography-tandem mass spectrometry-based method has been developed for the estimation of 4-hydroxyisoleucine (4-HI), a potent insulinotropic and hypolipidemic agent. The extraction of 4-HI from plasma was accomplished by the protein precipitation technique using l-isoleucine as an internal standard. The separation of analytes was achieved with a mobile phase consisting of acetonitrile and 0.1% formic acid in an isocratic flow system on a BEH Shield RP-18 column (150 mm × 2.1 mm, 1.7 µm). 4-HI and l-isoleucine were detected using an electrospray ionization (ESI) ion source, using multiple reaction monitoring (MRM) in positive ion mode. The precursor to product ion transitions of 4-HI and l-isoleucine were found at m/z values of 148.19 > 74.02 and 132.17 > 69.04, respectively. As per the guidelines for bioanalytical methods, all validation parameter results were within the acceptable range. The method exhibited a robust and reproducible linearity range of 1-5000 ng mL-1 with a coefficient of regression of 0.9999. The method was successfully applied for the estimation of pharmacokinetic parameters after oral administration of 4-HI (10 mg kg-1) in Wistar rats, by using Thoth Pro (version: 4.3) software. Herein, the two-compartment model was statistically fitted based on AIC and SBC values for evaluation of the pharmacokinetic parameters of 4-HI. Pharmacodynamic studies were also performed by measuring the levels of triglyceride and total cholesterol, and showed that the pharmacokinetic and pharmacodynamic data of 4-HI correlated with each other.

Associating Psychotic Symptoms with Altered Brain Anatomy in Psychotic Disorders Using Multidimensional Item Response Theory Models.

Reduced cortical thickness has been demonstrated in psychotic disorders, but its relationship to clinical symptoms has not been established. We aimed to identify the regions throughout neocortex where clinical psychosis manifestations correlate with cortical thickness. Rather than perform a traditional correlation analysis using total scores on psychiatric rating scales, we applied multidimensional item response theory to identify a profile of psychotic symptoms that was related to a region where cortical thickness was reduced. This analysis was performed using a large population of probands with psychotic disorders (N = 865), their family members (N = 678) and healthy volunteers (N = 347), from the 5-site Bipolar-Schizophrenia Network for Intermediate Phenotypes. Regional cortical thickness from structural magnetic resonance scans was measured using FreeSurfer; individual symptoms were rated using the Positive and Negative Syndrome Scale, Montgomery-Asberg Depression Rating Scale, and Young Mania Rating Scale. A cluster of cortical regions whose thickness was inversely related to severity of psychosis symptoms was identified. The regions turned out to be located contiguously in a large region of heteromodal association cortex including temporal, parietal and frontal lobe regions, suggesting a cluster of contiguous neocortical regions important to psychosis expression. When we tested the relationship between reduced cortical surface area and high psychotic symptoms we found no linked regions describing a related cortical set.

NRXN1 is associated with enlargement of the temporal horns of the lateral ventricles in psychosis.

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E-10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E-8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.

Using machine learning to explain the heterogeneity of schizophrenia. Realizing the promise and avoiding the hype.

Despite extensive research and prodigious advances in neuroscience, our comprehension of the nature of schizophrenia remains rudimentary. Our failure to make progress is attributed to the extreme heterogeneity of this condition, enormous complexity of the human brain, limitations of extant research paradigms, and inadequacy of traditional statistical methods to integrate or interpret increasingly large amounts of multidimensional information relevant to unravelling brain function. Fortunately, the rapidly developing science of machine learning appears to provide tools capable of addressing each of these impediments. Enthusiasm about the potential of machine learning methods to break the current impasse is reflected in the steep increase in the number of scientific publication about the application of machine learning to the study of schizophrenia. Machine learning approaches are, however, poorly understood by schizophrenia researchers and clinicians alike. In this paper, we provide a simple description of the nature and techniques of machine learning and their application to the study of schizophrenia. We then summarize its potential and constraints with illustrations from six studies of machine learning in schizophrenia and address some common misconceptions about machine learning. We suggest some guidelines for researchers, readers, science editors and reviewers of the burgeoning machine learning literature in schizophrenia. In order to realize its enormous promise, we suggest the need for the disciplined application of machine learning methods to the study of schizophrenia with a clear recognition of its capability and challenges accompanied by a concurrent effort to improve machine learning literacy among neuroscientists and mental health professionals.

Who benefits from percutaneous closure of patent foramen ovale vs medical therapy for stroke prevention? In-depth and updated meta-analysis of randomized trials.

BACKGROUND: A few randomized clinical trials (RCT) and their meta-analyses have found patent foramen ovale closure (PFOC) to be beneficial in prevention of stroke compared to medical therapy. Whether the benefit is extended across all groups of patients remains unclear. AIM: To evaluate the efficacy and safety of PFOC vs medical therapy in different groups of patients presenting with stroke, we performed this meta-analysis of RCTs. METHODS: Electronic search of PubMed, EMBASE, Cochrane Central, CINAHL and ProQuest Central and manual search were performed from inception through September 2018 for RCTs. Ischemic stroke (IS), transient ischemic attack (TIA), a composite of IS, TIA and systemic embolism (SE), mortality, major bleeding, atrial fibrillation (AF) and procedural complications were the major outcomes. Random-effects model was used to perform analyses. RESULTS: Meta-analysis of 6 RCTs including 3560 patients showed that the PFOC, compared to medical therapy reduced the risk of IS [odds ratio: 0.34; 95% confidence interval: 0.15-0.78; P = 0.01] and the composite of IS, TIA and SE [0.55 (0.32-0.93); P = 0.02] and increased the AF risk [4.79 (2.35-9.77); P < 0.0001]. No statistical difference was observed in the risk of TIA [0.86 (0.54-1.38); P = 0.54], mortality [0.74 (0.28-1.93); P = 0.53] and major bleeding [0.81 (0.42-1.56); P = 0.53] between two strategies. Subgroup analyses showed that compared to medical therapy, PFOC reduced the risk of stroke in persons who were males, ≤ 45 years of age and had large shunt or atrial septal aneurysm. CONCLUSION: In certain groups of patients presenting with stroke, PFOC is beneficial in preventing future stroke compared to medical therapy.

Hypogyrification and its association with cognitive impairment in children with 22q11.2 deletion Syndrome: A preliminary report.

22q11.2 Deletion Syndrome (22qDS) is a neurogenetic disorder resulting in cognitive deficits and hypogyrification, but relationships between these processes have not been established. 22qDS youth and healthy controls (HC) were administered a battery of cognitive tasks. Gyrification measurements were extracted from structural T1 scans using Freesurfer, contrasted between groups, and correlated to cognition. Data was adjusted for age, sex, socio-economic status and intracranial volume. 22qDS displayed significant hypogyrification which was associated with poorer executive functioning and verbal learning in orbitofrontal and anterior cingulate cortex. Our preliminary findings identified neurodevelopmental deficits in 22qDS shown by hypogyria, which relate to cognitive impairments.

Individual variation in brain network topology is linked to emotional intelligence.

BACKGROUND: Social cognitive ability is a significant determinant of functional outcome, and deficits in social cognition are a disabling symptom of psychotic disorders. The neurobiological underpinnings of social cognition are not well understood, hampering our ability to ameliorate these deficits. OBJECTIVE: Using 'resting state' functional magnetic resonance imaging (rsfMRI) and a trans-diagnostic, data-driven analytic strategy, we sought to identify the brain network basis of emotional intelligence, a key domain of social cognition. METHODS: The study included 60 participants with a diagnosis of schizophrenia or schizoaffective disorder and 45 healthy controls. All participants underwent a rsfMRI scan. Emotional Intelligence was measured using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). A connectome-wide analysis examined how each individual brain voxel's connectivity correlated with emotional intelligence using multivariate distance matrix regression (MDMR). RESULTS: We identified a region in the left superior parietal lobule (SPL) where individual network topology is linked to emotional intelligence. Specifically, in high scoring individuals, this region is a node of the Default Mode Network and in low scoring individuals, it is a node of the Dorsal Attention Network. This relationship was observed in both schizophrenia and healthy comparison participants. CONCLUSION: Prior studies have demonstrated individual variance in the topology of canonical resting state networks but the cognitive or behavioral relevance of these differences has largely been undetermined. We observe that the left SPL, a region of high individual variance at the cytoarchitectonic level, also demonstrates individual variance in its association with large scale resting-state networks and that network topology is linked to emotional intelligence.

Clinical psychopathology in youth at familial high risk for psychosis.

AIM: While the course of psychopathology has been explored from an index mental health diagnosis onwards, there are few detailed, prospective studies of the occurrence of clinical psychopathology in youth with familial risk for severe mental illnesses such as psychosis. We sought to describe the appearance of Axis I psychopathology in a unique sample of adolescents with a family history of schizophrenia (FHR). METHODS: One hundred and sixty two first- and second-degree relatives (mean age 15.7 ± 3.6; range 8-25) of probands with schizophrenia or schizoaffective disorder were assessed at baseline and annual intervals for up to 3 years, focusing on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) Axis I psychopathology. RESULTS: Fourteen individuals (8.6%) developed a psychotic disorder. One hundred and five subjects (65%) met criteria for an Axis I disorder over the course of the study, the most common of which was a depressive episode (40 subjects; 25%). Of the 148 individuals who did not develop psychosis, 91 (61%) had one or more Axis I disorders compared with 10/14 converters who had a comorbid Axis I disorder (71%). Ordered by increasing age of onset, diagnoses included cognitive and externalizing disorders, anxiety disorders, affective disorders, substance use disorders and psychotic disorders. CONCLUSIONS: In addition to an elevated risk of psychosis, young FHR relatives manifest a broad range of non-psychotic Axis I psychopathology in childhood and adolescence. This breadth of diagnoses has implications for the structure and function of mental health services for young people.

VEGFA GENE variation influences hallucinations and frontotemporal morphology in psychotic disorders: a B-SNIP study.

Vascular endothelial growth factor A (VEGFA) dysfunction may contribute to a number of pathological processes that characterize psychotic disorders. However, the influence of VEGFA gene variants on clinical and neuroimaging phenotypes in psychotic disorders has yet to be shown. In the present study, we examined whether different VEGFA gene variants influence psychosis risk, symptom severity, cognition, and brain volume. The study group included 480 probands (Bipolar I disorder with psychosis, n = 205; Schizoaffective disorder, n = 112; Schizophrenia, n = 163) and 126 healthy controls that were recruited across six sites in the B-SNIP consortium. VEGFA variants identified for analysis (rs699947, rs833070, and rs2146323) were quantified via SNP chip array. We assessed symptoms and cognition using standardized clinical and neuropsychological batteries. The dorsolateral prefrontal cortex (DLPFC), medial temporal lobe, and hippocampal volumes were quantified using FreeSurfer. In our sample, VEGFA rs2146323 A- carriers showed reduced odds of being a proband (p = 0.037, OR = 0.65, 95% CI = 0.43-0.98) compared to noncarriers, but not for rs699947 or rs833070. In probands, rs2146323 A- carriers demonstrated fewer hallucinations (p = 0.035, Cohen's d = 0.194), as well as significantly greater DLPFC (p < 0.05, Cohen's d = -0.21) and parahippocampal volumes (p < 0.01, Cohen's d = -0.27). No clinical or neuroimaging associations were identified for rs699947 or rs833070. In general, we found that the three SNPs exhibited several significant negative relationships between psychosis symptoms and brain structure. In the probands and control groups, positive relationships were identified between several cognitive and brain volume measures. The findings suggest VEGFA effects in the DLPFC and hippocampus found in animals may also extend to humans. VEGFA variations may have important implications in identifying dimensional moderators of function that could be targeted through VEGFA-mediated interventions.

Multivariate Relationships Between Cognition and Brain Anatomy Across the Psychosis Spectrum.

BACKGROUND: Cognitive and structural brain abnormalities range from mild to severe in psychosis. The relationships of specific cognitive functions to specific brain structures across the psychosis spectrum is less certain. METHODS: Participants (n = 678) with bipolar, schizoaffective, or schizophrenia psychoses and healthy control subjects were recruited via the Bipolar-Schizophrenia Network for Intermediate Phenotypes. The Schizo-Bipolar Scale was used to create a psychosis continuum (from purely affective to purely nonaffective). Canonical correlation between 14 cognitive measures and structural brain measures (gray matter volume, cortical thickness, cortical surface area, and local gyrification indices) for 68 neocortical regions yielded constructs that defined shared cognition-brain structure relationships. Canonical discriminant analysis was used to integrate these constructs and efficiently summarize cognition-brain structure relationships across the psychosis continuum. RESULTS: General cognition was associated with larger gray matter volumes and thicker cortices but smaller cortical surface area in frontoparietal regions. Working memory was associated with larger volume and surface area in frontotemporal regions. Faster response speed was associated with thicker frontal cortices. Constructs that captured general cognitive ability and working memory and their relationship to cortical volumes primarily defined an ordered psychosis spectrum (purely affective, least abnormal through purely nonaffective, and most abnormal). A construct that captured general cognitive ability and its relationship to cortical surface area differentiated purely affective cases from other groups. CONCLUSIONS: General cognition and working memory with cortical volume deviations characterized more nonaffective psychoses. Alternatively, affective psychosis cases with general cognitive deficits had deviations in cortical surface area, perhaps accounting for heterogeneous findings across previous studies.

Polygenic risk for schizophrenia and measured domains of cognition in individuals with psychosis and controls.

Psychotic disorders including schizophrenia are commonly accompanied by cognitive deficits. Recent studies have reported negative genetic correlations between schizophrenia and indicators of cognitive ability such as general intelligence and processing speed. Here we compare the effect of polygenetic risk for schizophrenia (PRSSCZ) on measures that differ in their relationships with psychosis onset: a measure of current cognitive abilities (the Brief Assessment of Cognition in Schizophrenia, BACS) that is greatly reduced in psychotic disorder patients, a measure of premorbid intelligence that is minimally affected by psychosis onset (the Wide-Range Achievement Test, WRAT); and educational attainment (EY), which covaries with both BACS and WRAT. Using genome-wide single nucleotide polymorphism (SNP) data from 314 psychotic and 423 healthy research participants in the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Consortium, we investigated the association of PRSSCZ with BACS, WRAT, and EY. Among apparently healthy individuals, greater genetic risk for schizophrenia (PRSSCZ) was significantly associated with lower BACS scores (r = -0.17, p = 6.6 × 10-4 at PT = 1 × 10-4), but not with WRAT or EY. Among individuals with psychosis, PRSSCZ did not associate with variations in any of these three phenotypes. We further investigated the association between PRSSCZ and WRAT in more than 4500 healthy subjects from the Philadelphia Neurodevelopmental Cohort. The association was again null (p > 0.3, N = 4511), suggesting that different cognitive phenotypes vary in their etiologic relationship with schizophrenia.

Comparison of manual compression and vascular hemostasis devices after coronary angiography or percutaneous coronary intervention through femoral artery access: A meta-analysis of randomized controlled trials.

OBJECTIVES: To compare the efficacy and safety of manual compression (MC) with vascular hemostasis devices (VHD) in patients undergoing coronary angiography (CA) or percutaneous coronary intervention (PCI) through femoral artery access. INTRODUCTION: The use of femoral artery access for coronary procedures may result in access-related complications, prolonged immobility and discomfort for the patients. MC results in longer time-to-hemostasis (TTH) and time-to-ambulation (TTA) compared to VHDs but its role in access-related complications remains unclear in patients undergoing coronary procedures. METHODS: We searched MEDLINE, EMBASE, Cochrane CENTRAL and relevant references for English language randomized controlled trials (RCT) from inception through September 30, 2016. We performed the meta-analysis using random effects model. The outcomes were time-to-hemostasis, time-to-ambulation, major bleeding, large hematoma >5cm, pseudoaneurysm and other adverse events. RESULTS: The electronic database search resulted in a total of 44 RCTs with a total of 18,802 patients for analysis. MC, compared to VHD resulted in longer TTH [mean difference (MD): 11.21min; 95% confidence interval (CI) 8.13-14.29; P<0.00001] and TTA [standardized mean difference: 1.2 (0.79-1.62); P<0.00001] along with excess risk of hematoma >5cm formation [risk ratio (RR): 1.38 (1.15-1.67); P=0.0008]. MC resulted in similar risk of major bleeding [1.01 (0.64-1.60); P=0.95] pseudoaneurysm [0.99 (0.75-1.29); P=0.92], infections [0.52 (0.25-1.10); P=0.09], need of surgery [0.60 (0.29-1.22); P=0.16), AV fistula [0.93 (0.68-1.27); P=0.63] and ipsilateral leg ischemia [0.95 (0.57-1.60); P=0.86] compared to VHD. CONCLUSION: Manual compression increase time-to-hemostasis, time-to-ambulation and risk of hematoma formation compared vascular hemostasis devices.

A comparison of standard versus low dose heparin on access-related complications after coronary angiography through radial access: A meta-analysis of randomized controlled trials.

BACKGROUND: Transradial access (TRA) is preferred for coronary angiography (CA) or percutaneous coronary intervention due to reduced access-related complications, and mortality especially for patients with ST elevation myocardial infarction. Radial artery occlusion (RAO) is a known complication of TRA, and precludes its use as a future access site, conduit for coronary artery bypass grafting or for hemodialysis fistula placement. Although a standard dose (SD) heparin of 5000 Units is used during TRA, the risks of RAO and hematoma compared to lower dose (LD) remain unclear. To compare the risks of RAO and hematoma using SD vs. LD heparin after CA through TRA, we performed a meta-analysis of randomized controlled trials (RCT). METHODS: We searched PubMed, EMBASE, CINAHL and CENTRAL for RCTs since inception through 06/30/2017 and used random effects model for analysis. The outcomes analyzed were RAO, hematoma formation and radial artery compression time (RACT). RESULTS: We identified a total of 6 RCTs with a total of 2239 patients. SD heparin resulted in a trend toward a lower risk of RAO [4.2% vs. 10.7%; risk ratio (RR): 0.40, 95% confidence interval (CI): 0.16-1.0; P=0.05], a trend toward increased risk of hematoma [2.2% vs. 1.1%; 1.83 (0.91-3.66); P=0.09], and a longer duration of RACT [mean difference: 9.64min (4.01-15.28); P=0.0008] compared to LD. CONCLUSIONS: The current meta-analysis showed a trend towards reduction in the risk of RAO with the use of standard dose heparin. Larger randomized trials should explore the appropriate dosing of heparin to prevent radial artery occlusion.

Genetic analysis of deep phenotyping projects in common disorders.

Several studies of complex psychotic disorders with large numbers of neurobiological phenotypes are currently under way, in living patients and controls, and on assemblies of brain specimens. Genetic analyses of such data typically present challenges, because of the choice of underlying hypotheses on genetic architecture of the studied disorders and phenotypes, large numbers of phenotypes, the appropriate multiple testing corrections, limited numbers of subjects, imputations required on missing phenotypes and genotypes, and the cross-disciplinary nature of the phenotype measures. Advances in genotype and phenotype imputation, and in genome-wide association (GWAS) methods, are useful in dealing with these challenges. As compared with the more traditional single-trait analyses, deep phenotyping with simultaneous genome-wide analyses serves as a discovery tool for previously unsuspected relationships of phenotypic traits with each other, and with specific molecular involvements.

Subcortical surface shape in youth at familial high risk for schizophrenia.

Abnormalities in the subcortical brain regions that support cognitive functions have been reported in schizophrenia. Relatives of those with schizophrenia often present with psychosis-like traits (schizotypy) and similar cognition as those with schizophrenia. To evaluate the relationships between subcortical structure, schizotypy, and cognitive function, we assessed shape and volume of the hippocampus, amygdala and thalamus in untreated youth at familial high risk for schizophrenia (HRSZ). The sample consisted of 66 HRSZ and 69 age-matched healthy controls (HC). Subjects' cognitive functions and schizotypy were assessed, and T1-weighted brain MRI were analyzed using the FSL software FIRST. The right hippocampus and right amygdala showed significantly increased concavity (inward displacement) in HRSZ compared to HC. While regional subcortical shape displacements were significantly correlated with sustained attention and executive function scores in HC, fewer correlations were seen in HRSZ. This suggests a possible alteration of the local structure-function relationship in subcortical brain regions of HRSZ for these cognitive domains, which could be related to anomalous plasticity.